The publication of the International application WO 97/23202 discloses phenyl-N-acyl derivatives of amines of general formula (XV)

which, among the others, covers 3-(p-hydroxyphenyl)-propionyl phenylethylamine, 3-(p-hydroxyphenyl)-propionyltyramine and 3-phenylpropionyl phenylethylamine (compounds IX, X, XI of the present invention, respectively). This publication discloses synthesis of compounds of general formula (XV) and use thereof as selective ligands of NMDA receptors subtypes useful for treating chronic pain, migraine headache as well as anesthetics. However, the indicated publication does not disclose or characterize specific structures corresponding to compounds X and XI of the present invention and any data supporting the declared activity are missed, and compound IX as an intermediate compound and synthesis thereof are disclosed in the process for preparation of other amines derivatives only.
Compounds IX, X and XI of the instant invention are also disclosed in earlier publications which became generally available to the public before the priority date of the International application WO 97/23202 indicated above, to be used for a different purpose.
3-(p-hydroxyphenyl)-propionyl phenylethylamine (IX) is disclosed in Jacobson K. A., Kirk K. L. New high-performance liquid chromatographic procedure for the detection and quantification of β-phenylethylamine.//J. Chromatography. 1987. V. 415. P. 124-128); 3-(p-hydroxyphenyl)-propionyl tyramine (X) is disclosed in R. B. Herbert, A. E. Kattah. The biosynthesis of Sceletium alkaloids in Sceletium subvelutinum L. Bolus.//Tetrahedron. 1990. V. 46. No 20. P. 7105-7118 and 3-phenyl propionyl phenylethylamine (XI) is disclosed in Maldonado E., Hernandez E., Ortega A. Amides, coumarine and other constituents from Simsia cronquistii.//Phytochem. 1992. P. 1413-1414.
The publication of the International application WO 97/23202 notes the possibility to use compounds of general formula (XV) for preventing some specific kinds of pain such as migraine headache, chronic pain as well as use thereof for anesthesia due to is the ability of said compounds to act as selective ligands of NMDA receptor subtypes. However, WO 97/23202 lacks any data supporting the declared activity of the this group of compounds and thus, the possibility to use such compounds for the indicated purpose on particular in vivo animal models and hence, conclusions about possible pharmacological effects are based exclusively on the assertion that all the compounds disclosed in the indicated International application are selective ligands of NMDA receptor subtypes.
The publication of the International application WO 97/23202 discloses a process for synthesis of 3-(p-hydroxyphenyl)-propionyl phenylethylamine (IX) using 1-hydroxybenzotriazole in the presence of N,N′-dicyclohexylcarbodiimide (DCC). A process for isolating and purifying said compound is not disclosed; among the physical-chemical constants, only melting point and 1H-NMR spectroscopy are given.
Article Jackson K. A., Kirk K. L. New high-performance liquid chromatographic procedure for the detection and quantification of β-phenylethylamine.//J. Chromatography. 1987. V. 415. P. 124-128 discloses the synthesis of 3-(p-hydroxyphenyl)-propionyl phenylethylamine (IX) using a modified N-oxysuccinimide ester of 3-(p-hydroxyphenyl)-propionic acid. Reaction is carried out in the mixture methanol—1M Na2HPO4, pH 8 (1:1), using sulfosuccinimidyl-3-(p-hydroxyphenyl)-propionate (the sulfated Bolton-Hunte reagent). The prepared product is characterized by the melting point only. In accordance with this article, 3-(p-hydroxyphenyl)-propionyl phenylethylamine prepared is used as an internal standard in an electrochemical detector in quantitative determination of intrinsic phenylethylamine level in body fluids using the HPLC method.
Article Herbert R. B., Kattah A. E. The biosynthesis of Sceletium alkaloids in Sceletium subvlutinum L. Bolus.//Tetrahedron. 1990. V. 46. No 20. P. 7105-7118 discloses the use of 3-(p-hydroxyphenyl)-propionyl tyramine (X) as an intermediate in the synthesis of Sceletium subvlutinum alkaloids as well as a process for synthesis thereof using the DCC method. A shortcoming of the instant process is the necessity of using column chromatography for purifying the target product with a comparatively low yield (about 48%).
The article Maldonado E., Hernandez E., Ortega A. Amides, coumarine and other constituents from Simsia cronquistii.//Phytochem. 1992. P. 1413-1414 discloses isolation of 3-phenyl propionyl phenylethylamine (XI) from an overland part of Simsia cronquistii plants and mass spectrometry, 1H-NMR spectroscopy data as well as the melting point are presented. No biological activity data are presented.
Synthesis of the compound XI using a condensing agent 4-(4,6-dimethoxy-1.3.5-triasin-2-yl)-4-methylmorpholine chloride (DMT-MM) is disclosed in Kumishima M., Kawachi C., Hioki K. et al. Formation of carboxamides by direct condensation of carboxylic acids and amines in alcohols using a new alcohol- and water-soluble condensing agent: DMT-MM.//Tetrahedron. 2001. V. 57. No 8. P. 1551-1558. A drawback of the given synthesis method is formation of a byproduct and the need in using preparative thin-layer chromatography to purify the target product that complicates the process and must inevitably lead to lowering yields. In spite of this, a high yield of the product (XI) making up 99% is indicated. Compound XI was synthesized to study applicability of the novel condensing agent DMT-MM.
Synthesis of tyrosine and phenylalanine amino acid derivatives such as 3-(p-hydroxyphenyl)-propionyltyrosine, phenylpropionyltyrosine, phenylacetyltyrosine, phenylpropionylalanine and phenylpropionyltyrosine methyl ester (compounds XIV, XV, XVI, XVIII and XXI of the present invention, respectively) and the study of their inhibiting effect on the TAN neuron identified in the ganglion of Achatina fulica farussae snail are disclosed in the articles Takeuchi H., Ariyoshi Y., Effects of N-beta-phenyl propionyl-L-tyrosine and its derivatives on the excitability of an identifiable giant neuron of Achatina fulica ferussac.//Comparative biochemistry and physiology. C: Comparative pharmacology. 1982. V. 72. No 2. P. 225-229 and Y. Ariyoshi, H. Takeuchi. Structure-activity relationships of N-β-phenylpropionyl-L-tyrosine and its derivatives on the inhibition of an identifiable giant neuron of an African giant snail.//Br. J. Pharmacol. 1982. V. 77. P. 631-639. In the article Y. Ariyoshi, H. Takeuchi. Structure-activity relationships of N-β-phenylpropionyl-L-tyrosine and its derivatives on the inhibition of an identifiable giant neuron of an African giant snail.//Br. J. Pharmacol. 1982. V. 77. P. 631-639. A typical technique of synthesis of compounds XIV, XV, XVI, XVIII and XXI by the method of activated N-oxysuccinimide esters using as an amine derivative tyrosine methyl ester with subsequent saponification thereof (for compounds XIV, XV, XVI, XVIII) is described, but physicochemical constants and an yields for said compounds are not given. Furthermore, synthesis of phenylacetyltyrosine (XV) with a high yield (94%) using 1-hydroxybenzotriasol and ethyl-3(3-dimethylamino)propylcarbodiimide using as starting compounds tyrosine ethyl ester and phenylpropionic acid with subsequent saponification of ethyl ester is disclosed in Tangpasuthadol V., Pendharkar S. M., Kohn J. Hydrolytic degradation of tyrosine-derived polycarbonates, a class of new biomaterials. Part I: Study of model compounds.//Biomaterials. 2000. V. 21. No 23. P. 2371-2378. 1H-NMR spectroscopy and melting point are presented.
Synthesis of phenylpropionyl phenylalanine (XVIII) by the chloroanhydride method in the presence of KOH is disclosed in Lustig N., Spiegelstain-Klarfeld H., Scheider E., Lichtenstein N. Phenylacetyl and phenylpropionyl amino acids. Their inhibitory effect on glutamine synthetase and their resistance to acylase. I.//Israel Journal of Chemistry. 1974. V. 12. No 3. P. 757-763. Melting point and elemental analysis are presented. Synthesis has been carried out to study inhibition degree of glutamine synthetase with compound XVIII.
Phenylpropionyltyrosine methyl ester (XXI) is mentioned in the JP patent 57193437 (Example 4), wherein synthesis thereof is implemented by the method of activated N-oxysuccinimide esters.
Synthesis of phenylacethylphenylalanine (XIX) similar to the synthesis of compound XVIII using chloroanhydride of phenylacetic acid is disclosed in Chen H. M., Hsu M. S., Huang L. J., et al. Effect of N-phenylacetyl L-amino acids on the differentiation of HL-60 cells.//Chinese Pharmaceutical Journal. 2001. V. 53. No 3. P. 157-167. The physicochemical characteristics of the target compound (melting point, 1H-NMR- and IR-spectroscopy, mass-spectroscopy) are presented. Phenylacethylphenylalanine (XIX) has been established to be an inductor of cellular differentiation.
3-(p-Hydroxyphenyl)-propionyltyrosine methyl ester (XX) is mentioned in the publication of the International application WO 97/23202, however, synthesis and physicochemical characteristics thereof are not presented. Compound (XX) is synthesized in order to use it as a monomer for the preparation of biodegradable polymers comparable with tissues.
A natural compound isolated from the symbiotic bacterium Xenorhabdus nematophilus, phenylacetylethylamin (XXIII) was synthesized by the chloroanhydride method and characterized by physicochemical data of 1H-NMR-, 13C-NMR- and IR-spectroscopy, mass-spectroscopy, melting point in the publication of the International application WO 01/49656. In vitro anti-tumor activity of compound XXIII has been investigated.
A general formula of the compounds disclosed in the publication of the International application WO 01/49656 covers also the other compounds of the instant invention: p-hydroxyphenylacetyltyramine, p-hydroxyphenylacetylphenylethylamine, and phenylacetyltyramine (compounds VII, VIII and VI of the instant invention, respectively). However, said publication does not disclose neither particular structural formulae of the indicated compounds nor synthesis thereof, nor physicochemical constants, nor biological activity data.
Phenylpropionyltyramine (XII) is mentioned in the article Takeuchi Hiroshi, Tamura Hiroko. The effects of aromatic amino acid derivatives on the excitability of an identifiable giant neuron of an African giant snail (Achatina fulica ferussac).//British Journal of Pharmacology. 1980. V. 69. No 1. P. 29-34, but without disclosure of synthesis thereof and physicochemical characteristics and purpose thereof.
In the article Garrett C. E., Jiang X., Prasad K, Pepic O. New observations on peptide bond formation using CDMT.//Tetrahedron Letters. 2002. V. 43, No 23. p, 4161-4165 phenylpropionylphenylalanine methyl ester (XXIV) and a process for synthesis thereof using the condensing agent 2-chloro-4,6-dimethoxy-1,3,5-triasine(CDMT) in the presence of N-methylmorpholine are disclosed. However, neither physicochemical characteristics of said compound, nor activity data are presented. Only notice as given that the instant process has the following advantages: a one-step synthesis and isolation of the product by precipitating with water results in a chromatographically pure product with a high yield of 90%.
Article Peric M., Vercek B., Petric A. ω-Diazoacetophenones as reagents for a mild and selective protection of an amino group.//Acta Chimica Slovenica. 1996. V. 43. No 2. P. 163-173 discloses synthesis of phenylacetyltyrosine methyl ester (XXII) an intermediate for peptide synthesis by condensation of phenylacetic acid with tyrosine methyl ester through formation of diasoketone. For purifying compound XXII, the use of column chromatography is obligatory. Melting point, 1H-NMR-spectroscopy and elemental analysis data are presented.
Phenmylacethylphenylalanine methyl ester (XXV) in accordance with Votano J. R., Altman J., Wilchek M., Potential use of biaromatic L-phenylalanyl derivatives as therapeutic agents in the treatment of sickle cell disease.//Proceedings of the National Academy of Sciences of the United States of America. 1984. V. 81. No 10. P. 3190-3194 was synthesized by the method of activated N-oxysuccinimide esters with subsequent purification by column chromatography. Physicochemical constants for said compound are not presented. In this article, compound XXV is an intermediate in synthesis of compound XIX which is being investigated as a candidate agent for treating sickle cell disease.
Furthermore, a method for enzymatic synthesis of compound XXV is known [Didziapetris R., Drabnig B., Schellenberger V., Jakubke H. D., Svedas V. Penicillin acylase-catalyzed protection and deprotection of amino groups as a promising approach in enzymatic peptide synthesis.//FEBS Letters. 1991. V. 287. No 1-2. P. 31-33].
Patent US 2003199566 (Bok S., Lee S., Jeong T., Phenolic acid derivatives and composition for preventing or treating blood lipid level-related diseases comprising the same) discloses a synthesis of 3-(p-hydroxyphenyl)-propionylphenylalanine (XVII) and 3-(p-hydroxyphenyl)-propionylphenylalanine methyl ester (XIII) is using 1-hydroxybenzotriasol and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in the presence of triethylamine. For preparing 3-(p-hydroxyphenyl)-propionylphenylalanine (XVII) saponification of compound (XIII) was further carried out with yield of the target product 78%. For the both compounds, data of 1H-NMR- and 13C-NMR-spectroscopy are presented. Compounds XVII and XIII are proposed to be used for preventing and treating diseases associated with blood level of lipids.
The International application publication WO 9952962 discloses 3-(p-hydroxyphenyl)propionyl-tyrosine benzyl ester (XXXIV). Melting point, data of 1H-NMR- and 13C-NMR-spectroscopy are presented.
Analgetic effect is known to be implemented in accordance with different mechanisms, in particular by inhibiting cyclooxigenase enzyme in the arachidonic acid cascade [Mashkovsky PPM Lekarstvennye sredstva (Medicaments).//Moscow. Novaya volna publishers. 2005. P. 163-164].
Non-narcotic analgetics and non-steroid anti-inflammatory agents possess the most manifested analgetic effect among the drugs lowering synthesis of algogenes. Non-narcotic analgetics are represented by salicilates (aspirin), pyrazolone derivatives (amidopirin, analgin) and para-aminophenol (paracetamol). To non-steroid anti-inflammatory agents belong derivatives of salicylic, acetic, propionic and antranylic acids. Non-narcotic analgetics and non-steroid anti-inflammatory agents along with analgetic effect possess anti-inflammatory and antipyretic action [Kukushkin M. L., Khitrov N. K. Obshchaya patologiya boli (General pathology of pain)/Moscow. Meditsina publishers. 2004. 142 pages]. Ulcerogeneity is the main side effect of non-steroid anti-inflammatory agents. A pro-spasmodic side effect is often observed in analgetics with different mechanism of action [Mashkovsky PPM Lekarstvennye sredstva (Medicaments).//Moscow. Novaya volna publishers. 2005. P. 154].
Anti-Parkinsonistic properties of non-steroid anti-inflammatory drugs sodium salicilate, indomethacine and pyroxycam are known [M. G. Kadieva, E. T. Oganesyan, S. Kh. Matsueva. Nejrotoxiny I sredstva dlya lecheniya bolezni Parkinsona. III. Sredstva, oposredovanno vlijaushchiye na dofaminergicheskuyu sistemu. (Neurotoxines and agents for treating Parkinson's disease. III. Agents with mediated effect on the dopaminergic system). Khimiko-pharmacevticheskij zhurnal. 2005. T. 39. No 11. S. 3-11]. Such activity is supposed to be partially realized being mediated through prostaglandins effecting the dopaminergic system.
Anti-serotonine drugs are also known to exert a positive effect on the dopamine system in Parkinson's disease promoting binding receptors to dopamine antagonists [M. G. Kadieva, E. T. Oganesyan, S. Kh. Matsueva. Nejrotoxiny I sredstva dlya lechenija bolezni Parkinsona (Neurotoxines and agents for treating Parkinson's disease) Khimiko-pharmacevticheskij zhurnal. 2005. T. 39. No 11. S. 3-11]. There are also other mechanisms of action of anti-Parkinsonistic drugs [Mashkovsky PPM Lekarstvennye sredstva (Medicaments).//Moscow. Novaya volna publishers. 2005. P. 138].
Depending on mechanism of action, antidepressants are subdivided into several groups, in particular monoamine oxydase inhibitors, tricyclic antioxidants, blockers of histamine, serotonin, cholecystokinin α-adrenoreceptors [Mashkovsky PPM Lekarstvennye sredstva (Medicaments).//Moscow. Novaya volna publishers. 2005. P. 109].
Since the use of the known antidepressants and structurally related compounds is accompanied by numerous serious side effects, then search for novel safe and efficient drugs having such action is actual. The use of the compounds of the present invention for preventing and treating depressive conditions was unknown.
Hypoxia is observed in numerous pathological states including disorders of the brain functions. Antioxidants improve utilization of circulating oxygen by the body enhancing resistance of the body to oxygen deficit. Drugs having such action are not numerous [Mashkovsky PPM Lekarstvennye sredstva (Medicaments).//Moscow. Novaya volna publishers. 2005. P. 729]. Many drugs including those controlling activity of the CNS additionally possess anti-hypoxic properties enhancing efficacy of their action. For the group of compounds of the present invention, anti-hypoxic effect had not been earlier disclosed.